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LONG TERM REMISSION: Challenges and controversies How and until when to treat? Christoph Thomssen Department of Gynaecology Martin-Luther-University Halle-Wittenberg Halle an der Saale / Germany Thursday, 2 November 2017 Audit I. 14:30-14:45 ABC4 AB Conference s treat hristoph Departm Ma

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Page 1: How and until when to treat? treat · 2017. 11. 28. · –ddEC q2wks*4 => docetaxel, Pertuzumab, Trastuzumab q3wks*4 followed by ... PLD): until progression ABC4 Conference A ce

LONG TERM REMISSION: Challenges and controversies

How and until when to treat?

Christoph Thomssen Department of Gynaecology Martin-Luther-University Halle-Wittenberg Halle an der Saale / Germany

Thursday, 2 November 2017 Audit I. 14:30-14:45

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hristophDepartmMa

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Potential Conflicts of Interest

• Amgen • Astra-Zeneca • Celgene • Genomic-Health • Lilly

• Nanostring • Novartis • Pfizer • Puma • Roche

Honoraria as compensation for lectures and advisory boards:

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General law:

ferenc

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• Long Term Remission: Definition, Frequency

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Long Term Remission after complete remission (CR) to chemotherapy

Greenberg PAC et al. J Clin Oncol 1996;14:2197-2205

N=263

5 years

CR 16.6% beyond 5 years

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Long Term Remission – Definition (HER2 positive mBC, 1st-line trastzuzumab)

Definition (acc. median): • Beyond 3 to 5 years

(4 yrs lower 5%-limit PFS) Predictors: • Younger age (<50 y at

treatment start) • High Performance (ECOG 0) • Initially complete response • No treatment interruption

(trastuzumab)

Unselected (Yeo 2015): • 12% beyond 5 yrs

Witzel I et al. BMC Cancer 2014, 14:806 Yeo B et al. The Breast 24 (2015) 751-757

268 patients with HER2-positive inoperable LABC or mBC without progression after at least 2 yrs

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Long Term Remission - Definition

• Threshold: 5 yrs is reasonable • Relevance depends on

–Biology / subtypes (chemotherapy rarely >9m) –Selection –Performance status –Patients preferences

• Incidence:

Unselected <15% no progression >5 yrs

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ER positive mBC

• Long term endocrine therapy • Maintenance endocrine therapy after

chemotherapy

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Page 9: How and until when to treat? treat · 2017. 11. 28. · –ddEC q2wks*4 => docetaxel, Pertuzumab, Trastuzumab q3wks*4 followed by ... PLD): until progression ABC4 Conference A ce

ER-positive disease (Luminal-like, HER2neg)

Endocrine therapy until progression

• High efficacy, low toxicity • Positive therapeutic index can be expected

for a long time interval • Clinical standard:

–Continous treatment as long as efficacy is given (LoE IV B)

–ET may maintain remission induced by CT

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References: Maintenance endocrine therapy after chemotherapy induced response 1. Sutherland S et al. Eur J Cancer. 2016 Dec;69:216-222. 2. Rossi S et al. Future Oncol. 2016 May;12(10):1299-307 (systematic review)

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Maintenance ET after response to capecitabine: A retrospective analysis

Median exposure to 1st-line Capecitabine: 6-8 courses à 3 weeks; Median F/U: 43 mths Chen XL et al. Chin J Cancer (2016) 35:39

N=138

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Conclusions: Endocrine therapy in LONG TERM REMISSION

• Biological rationale for long term ET –ET downregulates tumor cell proliferation, but

does not destroy tumor cells • ET as long as possible (until PD) (LoE IIIB)

–With long term remission, any switch to chemotherapy can be postponed

–Interruption („drug holidays“): •Short term feasible (derived from adjuvant data) •Long term (e.g. for pregnancy): individual decision

• Maintenance after chemotherapy (LoE IIB) –Retrospective data support the concept (& 1 RCT)

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• HER2-positive mBC

• Two cases

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Case 1: NB, 59 yrs

• 1999 BC, pT1c pN0 M0 G3 ER/PR-neg. HER2-pos. • 2001 proven metastases: sternal, parasternal,

lung; sternal/parasternal histologically proven; CT: disseminated lung metastases

• Paclitaxel / trastuzumab q1w 12 weeks, since then trastuzumab (q3w, now s.c.) and zoledronate (now q3m), meanwhile 190 months (>15 yrs !)

• Since 2002 clinically in complete remission (several CT scans); no toxicity (ECHO)

• Open question: Stop trastuzumab?

• Answer: The patient wants to continue

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Discontinuation of trastuzumab feasible?

Retrospective analysis, n=108, >2 y trastuzumab for mBC, 61% non-visceral; CR 52.8%, median PFS 11.2 yrs

Niikura N et al. Breast Cancer Res Treat. 2017 Sep 11. doi: 10.1007/s10549-017-4489-9. [Epub ahead of print]

Interruption of Trastuzumab before PD (n=27)

Long term remission: 3 rec./17

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LONG TERM REMISSION To stop or not to stop trastuzumab

PRO discontinuation • Substantially cardiotoxicity

(2% - 7%) • Long term remission after

discontinuation reported • Retrospective cohort

analyses favouring discontinuation – Niikura et al. 2017 (n=27) – Moilanen et al. 2017 (n=21)

CONTRA discontinuation • No prospective data / RCTs • Risk of selection bias in the

retrospective reports • Reports of early recurrence

after discontinuation • No predictors for relapse

after discontinuation • Reinduction – risk of

resistance • No reimbursement for re-

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Conclusion and Ontario Survey

Haq R et al. Curr Oncol. 2016 Apr;23(2):91-95

Conclusion: • To date, evidence does not support discontinuation

of trastuzumab in LONG TERM REMISSION (LoE IVC) • RCT based on world wide collaboration are needed Ontario Survey:

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Case 2: KJ, 37 yrs

• Invasive ductal BC (left upper inner quadrant) 2013/14 – cT2(3cm) pN1(1/1sn) G2 ER+(9/12) PR+(4/12) HER2+++ Ki-67 25 % – Isolated sternal metastasis M1 (OSS)

• Primary treatment: – ddEC q2wks*4 => docetaxel, Pertuzumab, Trastuzumab

q3wks*4 followed by– BCS with resection of the metastatic region of the sternum; – Radiotherapy incl. LAR/IMN and sternum

• Histopathology: – pCR breast, axilla and sternum (no tumour cells)

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Case 2 (de novo M1, HER2 pos.): Is the patient cured? Should she be considered as metastatic patient? How

long pertuzumab, how long trastuzumab?

Strong additional effect by pertuzumab

Weak additional effect by pertuzumab

Swain SM et al., Cleopatra Study Group. N. Engl J Med 2015; 372:724-34

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LONG TERM REMISSION with dual HER2-blockade: Conclusion

• In case of discussing discontinuation of

antiHER2-therapy, first consider pertuzumab to be discontinued for – Toxicity (diarrhea) – Possible reduced benefit after >3 yrs

(LoE: Expert opinion)

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• Chemotherapy

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LONG TERM REMISSION Chemotherapy: How and until when?

• Long term treatment often not feasible for acute toxicities – Combination regimen, docetaxel q3w – 6 to 9 courses recommended (as in the studies)

• Rather long tolerated regimen – Weekly regimen (paclitaxel, epirubicin, doxorubicin) up to

one year – Stop for cumulative cardiac toxicity or CIPN

• Well tolerated therapies –Daily regimen (e.g. capecitabine,

dose adjustment feasible) –Metronomic treatment (low dose cyclophos/mtx)

As long as therapeutic index is positive

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Maintenance Chemotherapy yes or no

Sánchez-Muñoz A et al. Expert Rev. Anticancer Ther. 8(12), 1907–12 (2008)

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Maintenance Chemotherapy yes or no

Comments: • Combination chemotherapy is not state-of-the-art • Long term toxicity must be balanced against

reduction of cancer symptoms

• Alternatives of low dose incl. metronomic chemotherapy have not been sufficiently studied – Capecitabine – Cyclophosphamide/methotrexate – Paclitaxel weekly – PEG-liposomal doxorubicin (?) ABC4 Con

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Summary - Long term remission? How and until when to treat?

• Endocrine therapy: – Until progression. – Maintenance therapy (e.g. ET after CT)

• Reasonable, some encouraging retrospective data

• Anti HER2-therapy: – Trastuzumab: Permanently. – Pertuzumab in addition to trastuzumab: As long as possible,

at least 3 years, limited by diarrhea • Chemotherapy:

– Combination therapy, toxic single agent: 6 to 9 courses – Anthracyclines: until cumulative toxicity is reached

(individual variations, regimen depending) – Less toxic agents (e.g. capecitabine, PLD): until progression

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General recommendation

• Treatment as long as therapeutic index is positive

(LoE: Expert opinion)

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Halle an der Saale, Germany

Halle an der Saale, Market Place The bronze age celestial chart of Nebra as an early guideline example (app. 2000 yrs. BC)

Source::left: www.Wikipedia.de; right: Landesamt für Denkmalpflege und Archäologie Sachsen-Anhalt, Landesmuseum für Vorgeschichte ABC4 Conference

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Long term remissions: Challenges and controversies Management issues: How and until when to treat?

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